June 2020

Nitrosamine impurities: How our experts are protecting public health against carcinogens


Mike Ludlow, Science Lead for Analytical and Materials Science Solutions (AMS) discusses how his expert team is protecting public health against overexposure to nitrosamines. Nitrosamines are carcinogenic impurities that have been detected in medicinal products, food items, including cured meat and fish, as well as in cigarette smoke and cosmetics. The AMS team investigates product contamination at all stages of the drug development process, from initial research and development to the routine stability testing of final products and production.

Hidden dangers

Nitrosamines are a well-known group of highly potent mutagenic and carcinogenic impurities, which regulatory authorities have highlighted as a cause for concern. These organic compounds can be found in the food we eat and the medication we take, and have been known to potentially increase the risk of cancer in those people exposed above an acceptable level and over long durations of time, notably in Zantac and related ranitidine products. Nitrosamines may be formed during the drug production process due to side reactions between starting materials and related degradants and impurities, plus solvents and catalysts, but there is also the potential for cross-contamination from the use of recycled solvents.

“Nitrosamines are considered potential highly potent genotoxic carcinogens, such that exposures even below the theoretical threshold of concern (TTC) limit of 0.15 µg / day may be associated with an unacceptable risk of carcinogenicity,” says Ludlow. Ludlow explains that following metabolic activation, nitrosamines can directly bind with DNA to form mutagenic adducts. In carcinogenicity studies, they have been seen to induce (at low doses and/or following just a single treatment) tumors in multiple organs and tissues, regardless of the species tested.

In 2019, the European Medicines Agency (EMA) requested that manufacturers perform a risk assessment on all drug products containing chemically synthesized active pharmaceutical ingredients (APIs). To confront this contamination issue head-on, the multi-disciplinary Analytical and Materials Science Solutions (AMS) at DDS, specialising in trace-level organic and inorganic pharmaceutical analysis, provides a wide range of current Good Manufacturing Practice (cGMP) analytical testing services, primarily supporting clients in the pharmaceutical and consumer healthcare sectors.

There remains no doubt that impurity profiling is necessary to protect the public against toxic impurities hazardous to health. The impact of any adverse test results can not only harm our health but could have severe consequences for the economy, leading to manufacturers being required to introduce modified production processes. “Concern around ranitidine has led to the FDA ordering the withdrawal of all prescription and over-the-counter versions of the product from the market. It is therefore vital that any analytical testing is performed using methodology that is proven to be both accurate and reliable,” says Ludlow.

Complex challenges

Nitrosamine detection and analysis requires expertise, specialized facilities, and sophisticated equipment that meets regulatory requirements. Key to DDS' success is its latest triple quadrupole LC-MS/MS technology, as recommended by the FDA and EMA regulatory bodies. LC-MS/MS combined with bespoke sample preparation techniques provides the necessary specificity and sensitivity needed for DDS to confirm the presence of nitrosamines and, where required, delivers an accurate determination of the levels of individual compounds. Nevertheless, challenges can still arise: “The area of nitrosamines testing is complex, there are a number of different potential analytes of concern to be targeted which need to be detected at very low levels in a wide variety of sample matrices. This means that robust sample preparation and analytical methodologies are vital,” explains Ludlow. “There is also the potential for accidental contamination as nitrosamines can be present in rubber products such as gloves and other laboratory consumables.”

DDS conducts world-renowned work to protect human health as well as offering a one-stop-shop service for drug impurity testing. “Our Impurity & Contamination Centre of Excellence provides high-quality cGMP pharmaceutical analysis, method development and validation support across a wide range of technique areas including chromatography, spectroscopy, inorganic analysis and physical properties testing,” says Ludlow.

Future outlooks

Looking ahead, Ludlow anticipates that industry risk assessment testing will extend further up the supply chain to investigate the potential sources of nitrosamine impurities, adding: ‘’This will involve increased analysis of raw materials and product excipients, and will require robust methodology and ever more reduced levels of detection.” Ludlow concludes that routine testing of drug products for the presence of nitrosamines is now likely to become a standard requirement of the regulatory authorities.